Synthesis and activity of polyacetylene substituted 2-hydroxy acids, esters, and amides against microbes of clinical importance

Article abstract of DOI:10.1016/j.bmcl.2010.06.020

A series of novel polyacetylene substituted 2-hydroxy acids and derivatives were prepared and characterized. Alkylation of butane-2,3-diacetal (BDA) protected glycolic acid with iodoalkyl substituted polyacetylene compounds gave the corresponding diacetal protected polyacetylene substituted 2-hydroxy acids. Diacetal deprotection through acid mediated hydrolysis, transesterification or aminolysis afforded the 2-hydroxy-polyacetylenic acid, ester or amide derivatives. Twenty one of these novel compounds were tested against 10 microbes of clinical importance and several of them showed good antimicrobial activity, in particular against Pseudomonas aeruginosa.

Full text of DOI:10.1016/j.bmcl.2010.06.020

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4555–4557
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and activity of polyacetylene substituted 2-hydroxy acids, esters,
and amides against microbes of clinical importance
Stella Kyi a, Nalin Wongkattiya c, Andrew C. Warden a, Michael S. O’Shea a, Margaret Deighton c,
Ian Macreadie b, Florian H. M. Graichen a,
*
a CSIRO, Molecular and Health Technologies, Bag 10, Clayton South, Vic. 3169, Australia
b CSIRO, Molecular and Health Technologies, Parkville, Vic. 3052, Australia
c RMIT University, Bundoora, Vic. 3083, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel polyacetylene substituted 2-hydroxy acids and derivatives were prepared and charac-
terized. Alkylation of butane-2,3-diacetal (BDA) protected glycolic acid with iodoalkyl substituted poly-
acetylene compounds gave the corresponding diacetal protected polyacetylene substituted 2-hydroxy
acids. Diacetal deprotection through acid mediated hydrolysis, transesterification or aminolysis afforded
the 2-hydroxy-polyacetylenic acid, ester or amide derivatives. Twenty one of these novel compounds
were tested against 10 microbes of clinical importance and several of them showed good antimicrobial
activity, in particular against Pseudomonas aeruginosa.
Received 13 April 2010
Revised 2 June 2010
Accepted 3 June 2010
Available online 10 June 2010
Keywords:
Polyacetylene
2-Hydroxy acids
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Microbes of clinical importance
Pseudomonas aeruginosa
Polyacetylenic lipids and their derivatives have been isolated
from a wide variety of species1–3 and are known for an array of inter-
esting properties.4,5 Compounds containing three conjugated unsat-
urated moieties, such as yne–ene–yne, yne–yne–ene and yne–yne–
yne polyacetylenics display a diverse range of biological effects
including cytotoxicity, antifungal, antimicrobial, herbicidal and
antibacterial activities.6–9 Thus, such polyacetylenic compounds
are of great interest to the pharmaceutical industry. A particularly
important area of interest is the discovery and development of novel
antimicrobial agents, since the number of effective antimicrobial
agents is declining due to increased antimicrobial resistance.
Moreover, advances in medicine have prolonged life, leading to an
aging population with decreased immunity and increased suscepti-
bility to hospital-acquired infections with multiresistant organisms,
which are difficult to treat with antimicrobial agents. As a part of our
ongoing studies into the chemistry and applications of polyacety-
lene containing molecules we recognised a hitherto unreported
class of polyacetylene substituted 2-hydroxy acids and deriva-
tives.10 Herein, we describe an efficient synthesis of novel 2-hydro-
xy-polyacetylenic acid, ester and amide derivatives and their
activity against ten species of Candida and bacteria.
1–11 were converted into the respective iodides 12–22 in good
yield following the literature procedures.17–19 We chose the iodo
leaving group (instead of bromo or chloro leaving groups) for the
subsequential alkylation based on our observations during the
synthesis of 2-hydroxy-diyne acids where we were able to show
good alkylation yield of glycolic acid butane-2,3-diacetal with
iodo-diyne compounds.16,17
The alkylation20–22 of glycolic acid BDA23,24 was carried out
with iodides 12–22 lithium bis(trimethylsilyl)amide (LHMDS)
(1.05 equiv) in THF at À78 °C.11,25 to afford products 23–33 in
moderate yield. Diacetal deprotection was accomplished by acid
mediated hydrolysis to give the 2-hydroxy-polyacetylenic acids
34–43 (Scheme 1) in quantitative yield and high purity.
Removal of the BDA protective group through transesterifica-
tion was carried out with 3-phenyl propanol (80 °C), isopropanol
(80 °C) and methanol (room temperature), giving the esters
44–47, respectively, in excellent yield. Aminolysis reactions were
carried out using each of benzylamine and 2-methyl-propanamine
as reagent and solvent providing the desired products 48 and 49,
respectively, in good yield. The purity of all final products was
greater than 95% by 1H NMR. A similar approach has been used
successfully for the synthesis of 2-hydroxy-diyne acids, amides
and esters.26,27
Our synthetic protocols and products are summarized in
Scheme 1 and Table 1. The polyacetylenic alcohols 1–11 were
prepared according to the literature procedures.9–16 The alcohols
Assay against Candida species—For the testing of antifungal
activity of 21 selected compounds, five clinically important species
of Candida (Candida albicans ATCC 90028, Candida glabrata ATCC
90030, Candida krusei ATCC 6258, Candida tropicalis ATCC 750,
* Corresponding author. Tel.: +61 3 9545 8133; fax: +61 3 9545 2552.
E-mail address: florian.graichen@csiro.au (F.H.M. Graichen).
0960-894X/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.020

4556
S. Kyi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4555–4557
Scheme 1. Synthesis of polyacetylene substituted 2-hydroxy acids and derivatives. Reagents and conditions: (a) PPh3, imidazole, I2, CH2Cl2, 1 h, À10 °C; (b) LHMDS, ( )
glycolic acid BDA, AcOH, 3 h, À78–20 °C; (c) CF3COOH/H2O, 20 °C; (d) HCl, 3-phenylpropanol, 80 °C; (e) HCl, i-PrOH, reflux; (f) HCl, MeOH, 20 °C; (g) benzylamine, 20 °C, then
TFA/H2O; (h) 2-methyl-propanamine, 20 °C, then TFA/H2O.
Table 1
Product
Y
R
R1
R2
R3
1, 12, 23, 34
yne–ene(cis)–yne
2, 13, 24, 35
3, 14, 25, 36
4, 15, 26,37
5, 16, 27, 38
6, 17, 28, 39
yne–ene(cis)–yne
yne–ene(cis)–yne
yne–ene(cis)–yne
ene(cis)–yne–yne
ene(trans)–yne–yne
7, 18, 29, 40
8, 19, 30, 41
9, 20, 31, 42
10, 21, 32, 43
ene(trans)–yne–yne
yne–yne–ene(cis)
yne–yne–yne
yne–yne–yne
11, 22, 33
yne–yne–ene(cis)
yne–yne–ene(cis)
44
45
yne–ene(cis)–yne
46
47
48
ene(trans)–yne–yne
ene(trans)–yne–yne
ene(trans)–yne–yne
49
yne–yne–ene(cis)

S. Kyi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4555–4557
4557
Table 2
species is resistant to most currently available antimicrobial agents
(Table 3).
Antifungal activities of selected compounds
We have described a convenient and high yielding methodology
to prepare polyacetylene substituted 2-hydroxy acids, esters and
amides 31–45 through the hydrolysis, transesterification or ami-
nolysis of diacetal protected polyacetylenic substituted 2-hydroxy
acids 21–30. Twenty one of these novel compounds were tested
against 10 microbes of clinical importance and in particular most
of the compounds showed strong activity against P. aeruginosa.
Additionally carboxylic acids 39–43, and methyl esters 44 and 47
showed activity against C. parapsilosis. This is a significant result,
since this P. aeruginosa is resistant to most currently available anti-
microbial agents. Future work will focus upon the biological activity
of other 2-hydroxy polyacetylene variants and the determination of
structure–activity relationships.
Products
IC50 range for Candida species (
l
M)
C. albicans C. glabrata
C. tropicalis C. krusei
C. parapsilosis
25
26
28
30
32
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
500–1000
500–1000
500–1000 ꢀ500
500–1000 500–1000
500–1000
500–1000
500–1000 500–1000
1000–2000
500–1000
500–1000
500–1000 ꢀ250
500–1000 ꢀ2
ꢀ1000
2–4
500–1000
500–1000
500–1000 2–4
500–1000 125–250
ꢀ30
Acknowledgments
We thank the GRDC (Grains Research and Development Corpo-
ration), Australia for financial support and Drs. Kathleen Turner
and Craig Francis for critical comments on the manuscript.
ꢀ1000
ꢀ500
ꢀ1000
Supplementary data
Blanks spaces indicate no inhibition.
Supplementary data (full experimental details and characteriza-
tion data for all new compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.bmcl.2010.06.020.
Table 3
Inhibition of bacterial growth
Products S. aureus
P. aeruginosa E. coli
S. pyogenes MRSA
ATCC 25923 ATCC 27853 ATCC 25922 ATCC 19615 clinical isolate
References and notes
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26
28
30
32
34
35
36
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38
39
40
41
42
43
44
45
46
47
48
49
+
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+
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À
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+
+
+
++
++
+++
++
+++
Reduction in optical density (OD595) compared with control without compound:
+++ >75%, ++ 50%, À 75%, + between 25% and 50%.
and Candida parapsilosis) were chosen. The results are summarized
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inactive.
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